The sixth season had star billing for twelve major roles, with nine of these were filled by returning main cast members from the fifth season. Martin Sheen receives the "and" credit for his role as President Josiah Bartlet, while Jimmy Smits receives a "with" credit for the episodes in which he appears. The rest of the ensemble are credited alphabetically, while Smits, Alda and Channing are only credited for the episodes in which he or she appears.

The sixth season opens with the Israeli and Palestinian delegations arriving at Camp David for peace talks. Despite problems at the summit, a deal is thrashed out by President Bartlet, but not before he fires Leo as chief of staff. Leo suffers a heart attack in the aftermath, leading to a re-shuffle of the White House staff. CJ Cregg becomes chief of staff but she finds it difficult to adapt, a fact not helped by the President's MS and the interference from the First Lady. Away from the White House, Josh convinces Texas Congressman Matt Santos to run for president, and after a shaky start, he finds himself in a three-way race for the Democratic nomination with Vice President Russell and former Vice President Hoynes. While the Republican primaries provide a clear winner in California Senator Arnold Vinick, the Democratic ticket is not finalized until the Democratic National Convention, at which Santos is chosen as presidential nominee, with Leo McGarry as his running mate. Meanwhile, someone at the White House has leaked national security information to reporter Greg Brock.

The world watches the aftermath of the Gaza attack on U.S. officials. The President learns that 82% of the American people, almost all of Congress, Vice President Bob Russell, Secretary of Defense Miles Hutchinson, the Joint Chiefs, and all of his staff besides C .J. Cregg and Kate Harper want him to launch retaliatory military strikes immediately. Meanwhile, he tries to arrange peace talks between the Israelis and Palestinians at Camp David. Finally, he strikes one of three suggested targets and readies for peace talks. Meanwhile, in Germany, Josh anxiously waits for Donna's recovery, leading to his feelings about her being questioned by Colin.

Josh returns to the US as Israeli-Palestinian peace talks at Camp David result in a momentous peace accord. President Bartlet fires White House Chief of Staff Leo McGarry, who was strongly against the talks. Moments later, Leo suffers a massive heart attack. ("The Birnam Wood" is a reference to the warning given to Macbeth in the Shakespeare play of the same name, in which he is warned that "Macbeth shall never vanquish'd be until / Great Birnam wood to high Dunsinane hill / Shall come against him.")

The senior staff clash with Congressional leaders on how to fund U.S. peacekeepers destined for the Middle East following the peace accord signed by Israel and the Palestinians. Donna returns to Washington as her injuries slowly heal. As Leo McGarry recovers from his heart attack, the Cabinet secretaries and senior staff members continually make missteps without a Chief of Staff. Bartlet eventually asks C. J. to become the new Chief of Staff.

C. J. Cregg begins her tenure as White House Chief of Staff, as Toby and Donna begin searching for a new Press Secretary. The Republic of Georgia offers to give the United States its stockpile of weapons-grade uranium. Josh meets with Representative Matthew Santos of Texas, who is retiring from Congress despite having only recently been elected to his seat. Santos will become a recurring character this season, as he begins a campaign for the Presidency.

Josh crashes an SUV into a hybrid vehicle, causing a public relations disaster. He meets with environmental supporters who berate the White House for doing too little to beef up laws in this area, including raising fuel emissions standards; Josh points out that they have had seven years of a hostile Congress. Annabeth Schott decides she can coach Toby to do the White House's press briefings. Kate confronts Donna about her experiences in Gaza.

While preparing the upcoming China summit, the Chinese are insulted by President Bartlet's acceptance of a Taiwanese independence movement flag at a prayer breakfast. Charlie must try and return the flag, which proves difficult. Meanwhile, C. J. has to agree to stipulations the Chinese are making in order to mend fences. Eventually at a performance by James Taylor that evening paying tribute to Sam Cooke, Jed confides to Abbey that he didn't see the flag. He couldn't tie his bow tie, hasn't been able to focus for over a day, and has lost the sight in his right eye. Meanwhile, former Vice-President John Hoynes asks Josh to run his presidential campaign.

At Zoey Bartlet's birthday party, magicians Penn and Teller appear to burn an American flag in the White House, prompting a publicity nightmare. Aboard Air Force One, Bartlet is stricken by a paralyzing MS episode, while Josh is approached to run the Vice President's presidential campaign. The Bartlet Administration offer Republican California Senator Arnold Vinick the position of the US Ambassador to the UN, but he turns it down and announces his candidacy for the Presidency instead. Governor Baker drops out of the Democratic nomination race, making Russell the clear front-runner.

In China, an impaired Bartlet is having trouble sitting through meetings following his MS attack. In Washington, a NASA functionary warns that an asteroid could strike Earth, while Josh wonders who should be the next guy to occupy the Oval Office and puts off a talk with Donna about her future until she finally quits her job.

A senator attaches a rider to the federal budget bill that would ban gay marriage, almost daring the President to veto it. Josh struggles with his replacement assistant. The Internet is rampant with a story that questions C.J.'s sexual orientation, and it is only fueled further when the White House refuses to dignify the allegations by putting out a statement. Donna joins the Vice President's campaign staff and heads for New Hampshire, while Santos decides that he will run for president if Josh will run his campaign.

On the day after Bartlet has given his last State of the Union address, Leo returns to the West Wing, figuring out what to do during the remaining 365 days of Barlet's term and writes "365" on a whiteboard. The tone of the episode is one of melancholy: Leo wanders about at first, seemingly aimless. He tries, and fails, to give a little speech to the team at the beginning of the episode before they scatter to the crises of the day, and is left in his new office watching old State of the Union addresses. After the U.S. Ambassador to Bolivia makes a speech about the upcoming elections there, a Socialist candidate surges in the polls. His followers later kidnap several American contractors working on drug eradication efforts. The President is harshly critical of the CIA Director and Kate points out that the contractors are prisoners of war. The First Lady has to attend a NASCAR NEXTEL Cup race at Martinsville. She is dreading it, until Annabeth briefs her on the "advantages". The President is sick and needs to take regular naps but, eventually, calls together the White House Staff, and Leo gets to finally speak. 364 days left, he says, and we can effect more change in any one of them than in a lifetime after leaving the White House forever. One by one, C. J., Toby, Charlie, Annabeth, Will, and Kate all suggest pressing concerns, changes they would like to see made in the time they have left.

The presidential candidates journey to Iowa, where Democrats Russell and Santos, and Republican Vinick, are all told by their handlers that when they appear before the corn growers association they must support subsidies for ethanol as fuel, regardless of their true feelings.

When a British passenger aircraft is accidentally shot down over Iran, causing an international crisis, C.J. battles with the First Lady over how much to let Bartlet's MS affect his schedule; Toby and constitutional scholar Lawrence Lessig work with Belarusian diplomats on a new constitution.

It is five days before the New Hampshire primary, and Josh is desperately trying to find a "silver bullet" that will get his candidate into the local debate between front-runners Russell and Hoynes. Then, Josh and Santos's disagreements over how to run the campaign come to a head when Santos hires Josh's ex-girlfriend Amy Gardner to help him prepare for the debate.

The loss of Josh Lyman to the Santos campaign has left the West Wing staff noticeably shorthanded. Meanwhile, a bill to combat drought conditions in the western U.S. presents problems for C. J., particularly in dealing with lobbyist Clifford Calley – whom Leo suggests as a replacement for Josh. Reporter Greg Brock investigates the possibility of the White House secretly supporting one of the presidential candidates. Senator Rafferty, a new contender, garners media attention with a ground-breaking speech, her words echoing President Bartlet's original health care plan known only to White House insiders. Asked about this, Toby, who since the recent death of his brother has been even more morose than usual, confronts Josh with his feelings of betrayal over Josh leaving. Their heated argument escalates into a short brawl. In the aftermath, Toby confesses to C. J. that his brother didn't die of cancer, but committed suicide – just "walking away" and leaving his loved ones behind. When Charlie tells Kate Harper that a man from his gym – who, eventually, turns out to be her ex-husband – asked about her, she's unsure if she's ready to date again, but seems to be attracted to Will Bailey.

Congressman Santos masterminds a plot to vote down Republican legislation in the House that would de-fund the President's program for stem cell research. A group of middle school children who are part of the Future Leaders for Democracy visit the White House and seek out Toby to discuss the voting age. Kate has to deal with a ridiculous impending invasion of Canada.

As Super Tuesday approaches, the three Democratic candidates battle it out to win California as the state legislature passes a bill that would prevent illegal immigrants from obtaining driver's licenses.

When speculations fly surrounding the nexus between communist Cuba and the United States, President Bartlet is propelled into a dubious conundrum- continue secret talks with Cuba's ailing dictator and lift the longstanding embargo or to yield to bipartisan political pressure and reaffirm decades-old sanctions. Meanwhile, Leo and Kate learn that they have more in common than politics when a distant memory of corrupted elections and bar room antics reveal a more intimate connection.

Senator Vinick wins the Republican nomination for presidency and begins working on his campaign. He gets political advice from Bruno about choosing a vice president and how to deal with the latest controversy of Vinick's church attendance, or lack thereof. Meanwhile the Democrats are stuck in a three-way race for enough delegates to win the Democratic nominations; Russell barely leads Santos and Hoynes is a distant third. Bartlet tries to show unity in the party by wrangling the candidates.

The clear organization of the Republican Convention is making the Democrats look in disarray as the three candidates continue to battle for a clear Democratic presidential nominee. Bartlet asks Leo to take control and organize the Democratic Convention. Meanwhile, the International Space Station has a leak and is losing oxygen which jeopardizes the lives of the three astronauts aboard and morality and mortality are examined. And a super-secret space shuttle might help them but it's considered too sensitive to reveal, until someone has a different idea.

Despite the best efforts of the White House, there is still no presidential nominee at the Democratic National Convention. As convention chair, Leo, sits down with representatives from the various campaigns, trying to organize proceedings despite in-fighting. Meanwhile, the lives of the three astronauts in the International Space Station are still hanging in the balance as their oxygen supply dwindles. The White House is trying to deal with the aftermath of the leaked rumor of a military shuttle that can be used to save them. With voices on all sides furious, President Bartlet demands that the leaker's name be on his desk by Friday and has given the task to Toby and Kate Harper. Back at the Convention, Josh is trying to work out where he can find the crucial votes needed to win Santos the nomination. With the belief that Hoynes' campaign is over, Josh asks his former boss to transfer his votes to Santos after the first ballot. Meanwhile, the Russell camp receives some bad news. At the White House, Kate and Toby meet the FBI agents in charge of interviewing people capable of leaking the shuttle information. The guilty party is facing ten years in a federal prison for releasing classified information. Santos eventually receives the presidential nomination. Josh tells Leo they still need a vice president and that the choice for the candidate is Leo.

The DVD release of season six was released by Warner Bros. first in the UK on September 26, 2005 and then in the US on May 9, 2006, after the season had completed broadcasting on television. As well as every episode from the season, the DVD release features bonus material including audio commentary on three episodes from directors and writers, and a documentary on Allison Janney's portrayal of C. J. Cregg.[44][45]